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MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance

Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic β cell destruction. Coxsackievirus B3 (CVB3) infection and melanoma differentiation-associated protein 5–dependent (MDA5-dependent) antiviral responses are linked with T1D development. Mutations within IFIH1, coding for MDA5, are...

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Autores principales: Blum, Samuel I., Taylor, Jared P., Barra, Jessie M., Burg, Ashley R., Shang, Qiao, Qiu, Shihong, Shechter, Oren, Hayes, Aleah R., Green, Todd J., Geurts, Aron M., Chen, Yi-Guang, Tse, Hubert M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9977297/
https://www.ncbi.nlm.nih.gov/pubmed/36512407
http://dx.doi.org/10.1172/jci.insight.157929
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author Blum, Samuel I.
Taylor, Jared P.
Barra, Jessie M.
Burg, Ashley R.
Shang, Qiao
Qiu, Shihong
Shechter, Oren
Hayes, Aleah R.
Green, Todd J.
Geurts, Aron M.
Chen, Yi-Guang
Tse, Hubert M.
author_facet Blum, Samuel I.
Taylor, Jared P.
Barra, Jessie M.
Burg, Ashley R.
Shang, Qiao
Qiu, Shihong
Shechter, Oren
Hayes, Aleah R.
Green, Todd J.
Geurts, Aron M.
Chen, Yi-Guang
Tse, Hubert M.
author_sort Blum, Samuel I.
collection PubMed
description Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic β cell destruction. Coxsackievirus B3 (CVB3) infection and melanoma differentiation-associated protein 5–dependent (MDA5-dependent) antiviral responses are linked with T1D development. Mutations within IFIH1, coding for MDA5, are correlated with T1D susceptibility, but how these mutations contribute to T1D remains unclear. Utilizing nonobese diabetic (NOD) mice lacking Ifih1 expression (KO) or containing an in-frame deletion within the ATPase site of the helicase 1 domain of MDA5 (ΔHel1), we tested the hypothesis that partial or complete loss-of-function mutations in MDA5 would delay T1D by impairing proinflammatory pancreatic macrophage and T cell responses. Spontaneous T1D developed in female NOD and KO mice similarly, but was significantly delayed in ΔHel1 mice, which may be partly due to a concomitant increase in myeloid-derived suppressor cells. Interestingly, KO male mice had increased spontaneous T1D compared with NOD mice. Whereas NOD and KO mice developed CVB3-accelerated T1D, ΔHel1 mice were protected partly due to decreased type I IFNs, pancreatic infiltrating TNF(+) macrophages, IFN-γ(+)CD4(+) T cells, and perforin(+)CD8(+) T cells. Furthermore, ΔHel1 MDA5 protein had reduced ATP hydrolysis compared with wild-type MDA5. Our results suggest that dampened MDA5 function delays T1D, yet loss of MDA5 promotes T1D.
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spelling pubmed-99772972023-03-02 MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance Blum, Samuel I. Taylor, Jared P. Barra, Jessie M. Burg, Ashley R. Shang, Qiao Qiu, Shihong Shechter, Oren Hayes, Aleah R. Green, Todd J. Geurts, Aron M. Chen, Yi-Guang Tse, Hubert M. JCI Insight Research Article Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic β cell destruction. Coxsackievirus B3 (CVB3) infection and melanoma differentiation-associated protein 5–dependent (MDA5-dependent) antiviral responses are linked with T1D development. Mutations within IFIH1, coding for MDA5, are correlated with T1D susceptibility, but how these mutations contribute to T1D remains unclear. Utilizing nonobese diabetic (NOD) mice lacking Ifih1 expression (KO) or containing an in-frame deletion within the ATPase site of the helicase 1 domain of MDA5 (ΔHel1), we tested the hypothesis that partial or complete loss-of-function mutations in MDA5 would delay T1D by impairing proinflammatory pancreatic macrophage and T cell responses. Spontaneous T1D developed in female NOD and KO mice similarly, but was significantly delayed in ΔHel1 mice, which may be partly due to a concomitant increase in myeloid-derived suppressor cells. Interestingly, KO male mice had increased spontaneous T1D compared with NOD mice. Whereas NOD and KO mice developed CVB3-accelerated T1D, ΔHel1 mice were protected partly due to decreased type I IFNs, pancreatic infiltrating TNF(+) macrophages, IFN-γ(+)CD4(+) T cells, and perforin(+)CD8(+) T cells. Furthermore, ΔHel1 MDA5 protein had reduced ATP hydrolysis compared with wild-type MDA5. Our results suggest that dampened MDA5 function delays T1D, yet loss of MDA5 promotes T1D. American Society for Clinical Investigation 2023-01-24 /pmc/articles/PMC9977297/ /pubmed/36512407 http://dx.doi.org/10.1172/jci.insight.157929 Text en © 2023 Blum et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Blum, Samuel I.
Taylor, Jared P.
Barra, Jessie M.
Burg, Ashley R.
Shang, Qiao
Qiu, Shihong
Shechter, Oren
Hayes, Aleah R.
Green, Todd J.
Geurts, Aron M.
Chen, Yi-Guang
Tse, Hubert M.
MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance
title MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance
title_full MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance
title_fullStr MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance
title_full_unstemmed MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance
title_short MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance
title_sort mda5-dependent responses contribute to autoimmune diabetes progression and hindrance
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9977297/
https://www.ncbi.nlm.nih.gov/pubmed/36512407
http://dx.doi.org/10.1172/jci.insight.157929
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